PROJECT SUMMARY Elderly patients are highly vulnerable to cardiac dysfunction while in sepsis. However, the mechanism underlying the increased risk of cardiac dysfunction in the elderly is poorly understood. Planned studies in this project will test the hypothesis that aging-related Klotho deficiency and TLR2 overexpression in the heart augment the myocardial inflammatory responses to sepsis and thereby exacerbate cardiac dysfunction. This hypothesis rests on the following novel findings: (1) aging exacerbates the myocardial/systemic inflammatory responses and cardiac dysfunction caused by either endotoxemia or sepsis; (2) the hyper- inflammatory phenotype of aging heart is characterized by elevated constitutive inflammation, Klotho deficiency and TLR2 overexpression; (3) TLR2 has a critical role in mediating the inflammatory responses, cardiac dysfunction and mortality in old septic mice; (4) recombinant Klotho is capable of suppressing TLR2 expression in aging heart and improving cardiac function in old septic mice; (5) anti-inflammatory cytokine IL-37 increases myocardial Klotho levels and is potent in protecting cardiac function in old septic mice. The major goals of this project are to elucidate the mechanism by which aging exerts an impact on myocardial expression of Klotho and TLR2, and to determine the role of Klotho deficiency and TLR2 overexpression in the mechanism underlying myocardial inflammatory responses and cardiac dysfunction caused by sepsis in old mice. We will pursue the following interrelated Specific Aims: (1) to test the hypothesis that Klotho deficiency plays an important role in aging-related myocardial hyper-inflammation and cardiac dysfunction in sepsis; (2) to test the hypothesis that lower Klotho levels in aging heart promote TLR2 expression; (3) to explore the therapeutic potential of anti-inflammatory cytokine IL-37 for organ protection in sepsis. The planned studies will provide insights into the mechanisms underlying the hyper-inflammatory responses of aging heart to infection and offer the basis for developing innovative strategies to protect aging heart against dysfunction caused by sepsis.